cAMP Phosphodiesterase Inhibitors Increases Nitric Oxide Production by Modulating Dimethylarginine Dimethylaminohydrolases
Pulmonary arterial hypertension is characterized by a progressive increase in pulmonary vascular resistance caused by endothelial dysfunction, inward vascular remodeling, and severe loss of precapillary pulmonary vessel cross-sectional area. Asymmetrical dimethylarginine (ADMA), an endogenous nitric...
Gespeichert in:
| Veröffentlicht in: | Circulation (New York, N.Y.) N.Y.), 2011-03, Vol.123 (11), p.1194-1204 |
|---|---|
| Hauptverfasser: | , , , , , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 1204 |
|---|---|
| container_issue | 11 |
| container_start_page | 1194 |
| container_title | Circulation (New York, N.Y.) |
| container_volume | 123 |
| creator | PULLAMSETTI, Soni Savai SAVAI, Rajkumar SEEGER, Werner GRIMMINGER, Friedrich SCHERMULY, Ralph Theo SCHAEFER, Martina Barbara WILHELM, Jochen GHOFRANI, Hossein Ardeschir WEISSMANN, Norbert SCHUDT, Christian FLEMING, Ingrid MAYER, Konstantin LEIPER, James |
| description | Pulmonary arterial hypertension is characterized by a progressive increase in pulmonary vascular resistance caused by endothelial dysfunction, inward vascular remodeling, and severe loss of precapillary pulmonary vessel cross-sectional area. Asymmetrical dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor, and its metabolizing enzyme dimethylarginine dimethylaminohydrolase (DDAH) play important roles in endothelial dysfunction. We investigated whether combined phosphodiesterase (PDE) 3 and 4 inhibition ameliorates endothelial function by regulating the ADMA-DDAH axis.
We investigated the effects of the PDE3/4 inhibitor tolafentrine in vitro on endothelial cell survival, proliferation, and apoptosis. Effects of tolafentrine on the endothelial nitric oxide synthase/nitric oxide pathway, DDAH expression, DDAH promoter activity, and cytokine release from endothelial cells and their subsequent influence on DDAH expression were investigated. In monocrotaline-induced pulmonary arterial hypertension in rats, the effects of inhaled tolafentrine on DDAH expression and activity were investigated. Real-time-polymerase chain reaction, immunocytochemistry, and PDE activity assays suggested high expression of PDE3 and PDE4 isoforms in endothelial cells. Treatment of endothelial cells with PDE3/4 inhibitor significantly decreased ADMA-induced apoptosis via a cAMP/PKA-dependent pathway by induction of DDAH2. Chronic nebulization of PDE3/4 inhibitor significantly attenuated monocrotaline-induced hemodynamic, gas exchange abnormalities, vascular remodeling, and right heart hypertrophy. Interestingly, PDE3/4 inhibitor treatment reduced ADMA and elevated nitric oxide/cGMP levels. Mechanistically, this could be attributed to direct modulatory effects of cAMP on the promoter region of DDAH2, which was consequently found to be increased in expression and activity. Furthermore, PDE3/4 inhibitor suppressed apoptosis in endothelial cells and increased vascularization in the lung.
Combined inhibition of PDE3 and 4 regresses development of pulmonary hypertension and promotes endothelial regeneration by modulating the ADMA-DDAH axis. |
| doi_str_mv | 10.1161/circulationaha.110.941484 |
| format | Article |
| fullrecord | <record><control><sourceid>pubmed_cross</sourceid><recordid>TN_cdi_crossref_primary_10_1161_CIRCULATIONAHA_110_941484</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>21382892</sourcerecordid><originalsourceid>FETCH-LOGICAL-c463t-6393627d4cb9c9a59bd23e80cf716341ef979b4ba70b9293815cd3c75293cb663</originalsourceid><addsrcrecordid>eNpFUMlOwzAUtBCIlsIvoHDgmOIti49RWRqpm1B7jmzHaYyyVHYqEb4eRy309OaNZkajAeAJwSlCIXqR2shjxTvdNrzkjoNTRhGN6RUYowBTnwaEXYMxhJD5EcF4BO6s_XJvSKLgFowwIjGOGR6DH5ksN96mbO2hbHOtbKcMt8pLm1IL3bXGOiiNcpz1VrozWnrrb50rb2Pa_CiHDp7ovaV7hkbN3nvVterKvuJmrxvdqAtR66Yt-9y01RB3D24KXln1cL4TsHt_287m_mL9kc6ShS9pSDo_JIyEOMqpFEwyHjCRY6JiKIsIhYQiVbCICSp4BAXDjMQokDmRUeCwFGFIJoCdcqVprTWqyA5G19z0GYLZsGc2Sz9nu0WyTderZJ44DmanPZ338eQ9HEWt8n_n34BO8HwWcCt5VRjeSG0vOgoxiiAjv4n7hI8</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype></control><display><type>article</type><title>cAMP Phosphodiesterase Inhibitors Increases Nitric Oxide Production by Modulating Dimethylarginine Dimethylaminohydrolases</title><source>MEDLINE</source><source>American Heart Association</source><source>Journals@Ovid Complete</source><source>EZB-FREE-00999 freely available EZB journals</source><creator>PULLAMSETTI, Soni Savai ; SAVAI, Rajkumar ; SEEGER, Werner ; GRIMMINGER, Friedrich ; SCHERMULY, Ralph Theo ; SCHAEFER, Martina Barbara ; WILHELM, Jochen ; GHOFRANI, Hossein Ardeschir ; WEISSMANN, Norbert ; SCHUDT, Christian ; FLEMING, Ingrid ; MAYER, Konstantin ; LEIPER, James</creator><creatorcontrib>PULLAMSETTI, Soni Savai ; SAVAI, Rajkumar ; SEEGER, Werner ; GRIMMINGER, Friedrich ; SCHERMULY, Ralph Theo ; SCHAEFER, Martina Barbara ; WILHELM, Jochen ; GHOFRANI, Hossein Ardeschir ; WEISSMANN, Norbert ; SCHUDT, Christian ; FLEMING, Ingrid ; MAYER, Konstantin ; LEIPER, James</creatorcontrib><description>Pulmonary arterial hypertension is characterized by a progressive increase in pulmonary vascular resistance caused by endothelial dysfunction, inward vascular remodeling, and severe loss of precapillary pulmonary vessel cross-sectional area. Asymmetrical dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor, and its metabolizing enzyme dimethylarginine dimethylaminohydrolase (DDAH) play important roles in endothelial dysfunction. We investigated whether combined phosphodiesterase (PDE) 3 and 4 inhibition ameliorates endothelial function by regulating the ADMA-DDAH axis.
We investigated the effects of the PDE3/4 inhibitor tolafentrine in vitro on endothelial cell survival, proliferation, and apoptosis. Effects of tolafentrine on the endothelial nitric oxide synthase/nitric oxide pathway, DDAH expression, DDAH promoter activity, and cytokine release from endothelial cells and their subsequent influence on DDAH expression were investigated. In monocrotaline-induced pulmonary arterial hypertension in rats, the effects of inhaled tolafentrine on DDAH expression and activity were investigated. Real-time-polymerase chain reaction, immunocytochemistry, and PDE activity assays suggested high expression of PDE3 and PDE4 isoforms in endothelial cells. Treatment of endothelial cells with PDE3/4 inhibitor significantly decreased ADMA-induced apoptosis via a cAMP/PKA-dependent pathway by induction of DDAH2. Chronic nebulization of PDE3/4 inhibitor significantly attenuated monocrotaline-induced hemodynamic, gas exchange abnormalities, vascular remodeling, and right heart hypertrophy. Interestingly, PDE3/4 inhibitor treatment reduced ADMA and elevated nitric oxide/cGMP levels. Mechanistically, this could be attributed to direct modulatory effects of cAMP on the promoter region of DDAH2, which was consequently found to be increased in expression and activity. Furthermore, PDE3/4 inhibitor suppressed apoptosis in endothelial cells and increased vascularization in the lung.
Combined inhibition of PDE3 and 4 regresses development of pulmonary hypertension and promotes endothelial regeneration by modulating the ADMA-DDAH axis.</description><identifier>ISSN: 0009-7322</identifier><identifier>EISSN: 1524-4539</identifier><identifier>DOI: 10.1161/circulationaha.110.941484</identifier><identifier>PMID: 21382892</identifier><identifier>CODEN: CIRCAZ</identifier><language>eng</language><publisher>Hagerstown, MD: Lippincott Williams & Wilkins</publisher><subject>3',5'-Cyclic-AMP Phosphodiesterases - antagonists & inhibitors ; 3',5'-Cyclic-AMP Phosphodiesterases - metabolism ; Amidohydrolases - antagonists & inhibitors ; Amidohydrolases - genetics ; Apoptosis - drug effects ; Arginine - analogs & derivatives ; Arginine - antagonists & inhibitors ; Arginine - metabolism ; Biological and medical sciences ; Blood and lymphatic vessels ; Cardiology. Vascular system ; Cell Proliferation - drug effects ; Cell Survival - drug effects ; Cells, Cultured ; Coronary heart disease ; Cyclic GMP - biosynthesis ; Cytokines - pharmacology ; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous ; Endothelial Cells - drug effects ; Endothelial Cells - enzymology ; Endothelial Cells - physiology ; Heart ; Hemodynamics - drug effects ; Humans ; Hypertension, Pulmonary - drug therapy ; Medical sciences ; Naphthyridines - pharmacology ; Nitric Oxide - biosynthesis ; Phosphodiesterase Inhibitors ; Promoter Regions, Genetic ; Pulmonary Gas Exchange - drug effects</subject><ispartof>Circulation (New York, N.Y.), 2011-03, Vol.123 (11), p.1194-1204</ispartof><rights>2015 INIST-CNRS</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c463t-6393627d4cb9c9a59bd23e80cf716341ef979b4ba70b9293815cd3c75293cb663</citedby><cites>FETCH-LOGICAL-c463t-6393627d4cb9c9a59bd23e80cf716341ef979b4ba70b9293815cd3c75293cb663</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,3687,27924,27925</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=24021709$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21382892$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>PULLAMSETTI, Soni Savai</creatorcontrib><creatorcontrib>SAVAI, Rajkumar</creatorcontrib><creatorcontrib>SEEGER, Werner</creatorcontrib><creatorcontrib>GRIMMINGER, Friedrich</creatorcontrib><creatorcontrib>SCHERMULY, Ralph Theo</creatorcontrib><creatorcontrib>SCHAEFER, Martina Barbara</creatorcontrib><creatorcontrib>WILHELM, Jochen</creatorcontrib><creatorcontrib>GHOFRANI, Hossein Ardeschir</creatorcontrib><creatorcontrib>WEISSMANN, Norbert</creatorcontrib><creatorcontrib>SCHUDT, Christian</creatorcontrib><creatorcontrib>FLEMING, Ingrid</creatorcontrib><creatorcontrib>MAYER, Konstantin</creatorcontrib><creatorcontrib>LEIPER, James</creatorcontrib><title>cAMP Phosphodiesterase Inhibitors Increases Nitric Oxide Production by Modulating Dimethylarginine Dimethylaminohydrolases</title><title>Circulation (New York, N.Y.)</title><addtitle>Circulation</addtitle><description>Pulmonary arterial hypertension is characterized by a progressive increase in pulmonary vascular resistance caused by endothelial dysfunction, inward vascular remodeling, and severe loss of precapillary pulmonary vessel cross-sectional area. Asymmetrical dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor, and its metabolizing enzyme dimethylarginine dimethylaminohydrolase (DDAH) play important roles in endothelial dysfunction. We investigated whether combined phosphodiesterase (PDE) 3 and 4 inhibition ameliorates endothelial function by regulating the ADMA-DDAH axis.
We investigated the effects of the PDE3/4 inhibitor tolafentrine in vitro on endothelial cell survival, proliferation, and apoptosis. Effects of tolafentrine on the endothelial nitric oxide synthase/nitric oxide pathway, DDAH expression, DDAH promoter activity, and cytokine release from endothelial cells and their subsequent influence on DDAH expression were investigated. In monocrotaline-induced pulmonary arterial hypertension in rats, the effects of inhaled tolafentrine on DDAH expression and activity were investigated. Real-time-polymerase chain reaction, immunocytochemistry, and PDE activity assays suggested high expression of PDE3 and PDE4 isoforms in endothelial cells. Treatment of endothelial cells with PDE3/4 inhibitor significantly decreased ADMA-induced apoptosis via a cAMP/PKA-dependent pathway by induction of DDAH2. Chronic nebulization of PDE3/4 inhibitor significantly attenuated monocrotaline-induced hemodynamic, gas exchange abnormalities, vascular remodeling, and right heart hypertrophy. Interestingly, PDE3/4 inhibitor treatment reduced ADMA and elevated nitric oxide/cGMP levels. Mechanistically, this could be attributed to direct modulatory effects of cAMP on the promoter region of DDAH2, which was consequently found to be increased in expression and activity. Furthermore, PDE3/4 inhibitor suppressed apoptosis in endothelial cells and increased vascularization in the lung.
Combined inhibition of PDE3 and 4 regresses development of pulmonary hypertension and promotes endothelial regeneration by modulating the ADMA-DDAH axis.</description><subject>3',5'-Cyclic-AMP Phosphodiesterases - antagonists & inhibitors</subject><subject>3',5'-Cyclic-AMP Phosphodiesterases - metabolism</subject><subject>Amidohydrolases - antagonists & inhibitors</subject><subject>Amidohydrolases - genetics</subject><subject>Apoptosis - drug effects</subject><subject>Arginine - analogs & derivatives</subject><subject>Arginine - antagonists & inhibitors</subject><subject>Arginine - metabolism</subject><subject>Biological and medical sciences</subject><subject>Blood and lymphatic vessels</subject><subject>Cardiology. Vascular system</subject><subject>Cell Proliferation - drug effects</subject><subject>Cell Survival - drug effects</subject><subject>Cells, Cultured</subject><subject>Coronary heart disease</subject><subject>Cyclic GMP - biosynthesis</subject><subject>Cytokines - pharmacology</subject><subject>Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous</subject><subject>Endothelial Cells - drug effects</subject><subject>Endothelial Cells - enzymology</subject><subject>Endothelial Cells - physiology</subject><subject>Heart</subject><subject>Hemodynamics - drug effects</subject><subject>Humans</subject><subject>Hypertension, Pulmonary - drug therapy</subject><subject>Medical sciences</subject><subject>Naphthyridines - pharmacology</subject><subject>Nitric Oxide - biosynthesis</subject><subject>Phosphodiesterase Inhibitors</subject><subject>Promoter Regions, Genetic</subject><subject>Pulmonary Gas Exchange - drug effects</subject><issn>0009-7322</issn><issn>1524-4539</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpFUMlOwzAUtBCIlsIvoHDgmOIti49RWRqpm1B7jmzHaYyyVHYqEb4eRy309OaNZkajAeAJwSlCIXqR2shjxTvdNrzkjoNTRhGN6RUYowBTnwaEXYMxhJD5EcF4BO6s_XJvSKLgFowwIjGOGR6DH5ksN96mbO2hbHOtbKcMt8pLm1IL3bXGOiiNcpz1VrozWnrrb50rb2Pa_CiHDp7ovaV7hkbN3nvVterKvuJmrxvdqAtR66Yt-9y01RB3D24KXln1cL4TsHt_287m_mL9kc6ShS9pSDo_JIyEOMqpFEwyHjCRY6JiKIsIhYQiVbCICSp4BAXDjMQokDmRUeCwFGFIJoCdcqVprTWqyA5G19z0GYLZsGc2Sz9nu0WyTderZJ44DmanPZ338eQ9HEWt8n_n34BO8HwWcCt5VRjeSG0vOgoxiiAjv4n7hI8</recordid><startdate>20110322</startdate><enddate>20110322</enddate><creator>PULLAMSETTI, Soni Savai</creator><creator>SAVAI, Rajkumar</creator><creator>SEEGER, Werner</creator><creator>GRIMMINGER, Friedrich</creator><creator>SCHERMULY, Ralph Theo</creator><creator>SCHAEFER, Martina Barbara</creator><creator>WILHELM, Jochen</creator><creator>GHOFRANI, Hossein Ardeschir</creator><creator>WEISSMANN, Norbert</creator><creator>SCHUDT, Christian</creator><creator>FLEMING, Ingrid</creator><creator>MAYER, Konstantin</creator><creator>LEIPER, James</creator><general>Lippincott Williams & Wilkins</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope></search><sort><creationdate>20110322</creationdate><title>cAMP Phosphodiesterase Inhibitors Increases Nitric Oxide Production by Modulating Dimethylarginine Dimethylaminohydrolases</title><author>PULLAMSETTI, Soni Savai ; SAVAI, Rajkumar ; SEEGER, Werner ; GRIMMINGER, Friedrich ; SCHERMULY, Ralph Theo ; SCHAEFER, Martina Barbara ; WILHELM, Jochen ; GHOFRANI, Hossein Ardeschir ; WEISSMANN, Norbert ; SCHUDT, Christian ; FLEMING, Ingrid ; MAYER, Konstantin ; LEIPER, James</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c463t-6393627d4cb9c9a59bd23e80cf716341ef979b4ba70b9293815cd3c75293cb663</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>3',5'-Cyclic-AMP Phosphodiesterases - antagonists & inhibitors</topic><topic>3',5'-Cyclic-AMP Phosphodiesterases - metabolism</topic><topic>Amidohydrolases - antagonists & inhibitors</topic><topic>Amidohydrolases - genetics</topic><topic>Apoptosis - drug effects</topic><topic>Arginine - analogs & derivatives</topic><topic>Arginine - antagonists & inhibitors</topic><topic>Arginine - metabolism</topic><topic>Biological and medical sciences</topic><topic>Blood and lymphatic vessels</topic><topic>Cardiology. Vascular system</topic><topic>Cell Proliferation - drug effects</topic><topic>Cell Survival - drug effects</topic><topic>Cells, Cultured</topic><topic>Coronary heart disease</topic><topic>Cyclic GMP - biosynthesis</topic><topic>Cytokines - pharmacology</topic><topic>Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous</topic><topic>Endothelial Cells - drug effects</topic><topic>Endothelial Cells - enzymology</topic><topic>Endothelial Cells - physiology</topic><topic>Heart</topic><topic>Hemodynamics - drug effects</topic><topic>Humans</topic><topic>Hypertension, Pulmonary - drug therapy</topic><topic>Medical sciences</topic><topic>Naphthyridines - pharmacology</topic><topic>Nitric Oxide - biosynthesis</topic><topic>Phosphodiesterase Inhibitors</topic><topic>Promoter Regions, Genetic</topic><topic>Pulmonary Gas Exchange - drug effects</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>PULLAMSETTI, Soni Savai</creatorcontrib><creatorcontrib>SAVAI, Rajkumar</creatorcontrib><creatorcontrib>SEEGER, Werner</creatorcontrib><creatorcontrib>GRIMMINGER, Friedrich</creatorcontrib><creatorcontrib>SCHERMULY, Ralph Theo</creatorcontrib><creatorcontrib>SCHAEFER, Martina Barbara</creatorcontrib><creatorcontrib>WILHELM, Jochen</creatorcontrib><creatorcontrib>GHOFRANI, Hossein Ardeschir</creatorcontrib><creatorcontrib>WEISSMANN, Norbert</creatorcontrib><creatorcontrib>SCHUDT, Christian</creatorcontrib><creatorcontrib>FLEMING, Ingrid</creatorcontrib><creatorcontrib>MAYER, Konstantin</creatorcontrib><creatorcontrib>LEIPER, James</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><jtitle>Circulation (New York, N.Y.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>PULLAMSETTI, Soni Savai</au><au>SAVAI, Rajkumar</au><au>SEEGER, Werner</au><au>GRIMMINGER, Friedrich</au><au>SCHERMULY, Ralph Theo</au><au>SCHAEFER, Martina Barbara</au><au>WILHELM, Jochen</au><au>GHOFRANI, Hossein Ardeschir</au><au>WEISSMANN, Norbert</au><au>SCHUDT, Christian</au><au>FLEMING, Ingrid</au><au>MAYER, Konstantin</au><au>LEIPER, James</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>cAMP Phosphodiesterase Inhibitors Increases Nitric Oxide Production by Modulating Dimethylarginine Dimethylaminohydrolases</atitle><jtitle>Circulation (New York, N.Y.)</jtitle><addtitle>Circulation</addtitle><date>2011-03-22</date><risdate>2011</risdate><volume>123</volume><issue>11</issue><spage>1194</spage><epage>1204</epage><pages>1194-1204</pages><issn>0009-7322</issn><eissn>1524-4539</eissn><coden>CIRCAZ</coden><abstract>Pulmonary arterial hypertension is characterized by a progressive increase in pulmonary vascular resistance caused by endothelial dysfunction, inward vascular remodeling, and severe loss of precapillary pulmonary vessel cross-sectional area. Asymmetrical dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor, and its metabolizing enzyme dimethylarginine dimethylaminohydrolase (DDAH) play important roles in endothelial dysfunction. We investigated whether combined phosphodiesterase (PDE) 3 and 4 inhibition ameliorates endothelial function by regulating the ADMA-DDAH axis.
We investigated the effects of the PDE3/4 inhibitor tolafentrine in vitro on endothelial cell survival, proliferation, and apoptosis. Effects of tolafentrine on the endothelial nitric oxide synthase/nitric oxide pathway, DDAH expression, DDAH promoter activity, and cytokine release from endothelial cells and their subsequent influence on DDAH expression were investigated. In monocrotaline-induced pulmonary arterial hypertension in rats, the effects of inhaled tolafentrine on DDAH expression and activity were investigated. Real-time-polymerase chain reaction, immunocytochemistry, and PDE activity assays suggested high expression of PDE3 and PDE4 isoforms in endothelial cells. Treatment of endothelial cells with PDE3/4 inhibitor significantly decreased ADMA-induced apoptosis via a cAMP/PKA-dependent pathway by induction of DDAH2. Chronic nebulization of PDE3/4 inhibitor significantly attenuated monocrotaline-induced hemodynamic, gas exchange abnormalities, vascular remodeling, and right heart hypertrophy. Interestingly, PDE3/4 inhibitor treatment reduced ADMA and elevated nitric oxide/cGMP levels. Mechanistically, this could be attributed to direct modulatory effects of cAMP on the promoter region of DDAH2, which was consequently found to be increased in expression and activity. Furthermore, PDE3/4 inhibitor suppressed apoptosis in endothelial cells and increased vascularization in the lung.
Combined inhibition of PDE3 and 4 regresses development of pulmonary hypertension and promotes endothelial regeneration by modulating the ADMA-DDAH axis.</abstract><cop>Hagerstown, MD</cop><pub>Lippincott Williams & Wilkins</pub><pmid>21382892</pmid><doi>10.1161/circulationaha.110.941484</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0009-7322 |
| ispartof | Circulation (New York, N.Y.), 2011-03, Vol.123 (11), p.1194-1204 |
| issn | 0009-7322 1524-4539 |
| language | eng |
| recordid | cdi_crossref_primary_10_1161_CIRCULATIONAHA_110_941484 |
| source | MEDLINE; American Heart Association; Journals@Ovid Complete; EZB-FREE-00999 freely available EZB journals |
| subjects | 3',5'-Cyclic-AMP Phosphodiesterases - antagonists & inhibitors 3',5'-Cyclic-AMP Phosphodiesterases - metabolism Amidohydrolases - antagonists & inhibitors Amidohydrolases - genetics Apoptosis - drug effects Arginine - analogs & derivatives Arginine - antagonists & inhibitors Arginine - metabolism Biological and medical sciences Blood and lymphatic vessels Cardiology. Vascular system Cell Proliferation - drug effects Cell Survival - drug effects Cells, Cultured Coronary heart disease Cyclic GMP - biosynthesis Cytokines - pharmacology Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous Endothelial Cells - drug effects Endothelial Cells - enzymology Endothelial Cells - physiology Heart Hemodynamics - drug effects Humans Hypertension, Pulmonary - drug therapy Medical sciences Naphthyridines - pharmacology Nitric Oxide - biosynthesis Phosphodiesterase Inhibitors Promoter Regions, Genetic Pulmonary Gas Exchange - drug effects |
| title | cAMP Phosphodiesterase Inhibitors Increases Nitric Oxide Production by Modulating Dimethylarginine Dimethylaminohydrolases |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-03T20%3A42%3A49IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-pubmed_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=cAMP%20Phosphodiesterase%20Inhibitors%20Increases%20Nitric%20Oxide%20Production%20by%20Modulating%20Dimethylarginine%20Dimethylaminohydrolases&rft.jtitle=Circulation%20(New%20York,%20N.Y.)&rft.au=PULLAMSETTI,%20Soni%20Savai&rft.date=2011-03-22&rft.volume=123&rft.issue=11&rft.spage=1194&rft.epage=1204&rft.pages=1194-1204&rft.issn=0009-7322&rft.eissn=1524-4539&rft.coden=CIRCAZ&rft_id=info:doi/10.1161/circulationaha.110.941484&rft_dat=%3Cpubmed_cross%3E21382892%3C/pubmed_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_id=info:pmid/21382892&rfr_iscdi=true |